As a person ages the minimum distance from the eye at which an object will come into focus, provided distance vision is corrected or is excellent unaided, increases. For example, a 10 year-old can focus on an object or a “focal point” only three inches (0.072 meters) from their eye while still retaining excellent distance vision; a 40 year-old at six inches (0.15 meters); and a 60 year-old at an inconvenient 39 inches (1.0 meter). This condition of increasing minimum focal length in individuals with excellent unaided distance vision is called presbyopia, loosely translated as “old-man eye”.
Excellent unaided distance vision is also known as emmetropia. The inability to focus on distant focal points is known as myopia and the inability to focus on near focal points is known as hyperopia. Specifically, “distance” vision is considered any focal point 1 meter or more from the eye and near vision is any focal point less than 1 meter from the eye. The minimum focal length at which an object will come into focus is known as the “near point”. The change in focus from distance to the near point and any focal point in between is called accommodation. Accommodation is often measured in diopters. Diopters are calculated by taking the reciprocal of the focal length (in meters). For example, the decrease in accommodation from a 10 year-old eye to a 60 year-old eye is about 13 diopters (1±0.072 meters=13.89 diopters; 1±1 meter=1 diopter).
The highest incidence of first complaint of presbyopia occurs in people ages 42-44. Presbyopia occurs because as a person ages the eye's accommodative ability which uses near reflex-pupil constriction, convergence of the eyes and particularly ciliary muscle contraction decreases. This reduction in accommodation results in an inadequate change in the normal thickening and increased curvature of the anterior surface of the lens that is necessary for the shift in focus from distant objects to near objects. Important near focus tasks affected by presbyopia include viewing computer screens (21 inches) and reading print (16 inches).
Presbyopia is a normal and inevitable effect of ageing and is the first unmistakable sign for many in their forties that they are getting older. One study found that more than 1 billion people worldwide were presbyopic in 2005. This same study predicted that number to almost double by the year 2050. If everyone over the age of 45 is considered to be presbyopic, then an estimated 122 million people in the United States alone had presbyopia in 2010. As baby boomers reach the critical age, this number is only going to increase.
Presbyopia carries with it a stigma resulting from the limitation in ability to quickly function at many tasks requiring focusing at both distant and near points, which once occurred almost immediately. In the presbyopic patient, these tasks can be performed only by the use of eyeglasses, contact lenses or after undergoing invasive surgery. One such optical modification, the monovision procedure, can be executed with the use of glasses, contact lenses or even surgery. The monovision procedure corrects one eye for near focus and the other eye for distance focus. However, monovision correction is normally accompanied by loss of depth perception and distance vision particularly in dim light (e.g. night). Other surgical procedures that have been developed to relieve presbyopia include: (1) the implantation of intraocular lenses (INTRACOR®; registered trademark of Technolas Perfect Vision GMBH); (2) reshaping of the cornea (PresbyLASIK and conductive keratoplasty); (3) scleral band expansion; and (4) implantation of corneal inlays (Flexivue Microlens®; registered trademark of PresbiBio LLC, Kamra®; registered trademark of AcuFocus, Inc. and Vue+). Kamra® corneal inlays manufactured by AcuFocus work by inlaying a pinhole on the cornea to increase the depth of focus. A similar effect can be achieved with general miotic agents, such as pilocarpine (a non-selective muscarinic acetylcholine receptor agonist), carbachol (a non-selective muscarinic acetylcholine receptor agonist), and phospholine iodide (an acetylcholinesterase inhibitor). These general miotic agents trigger increased ciliary muscle contraction and induce accommodation of any remaining reserves, improving near vision at the expense of distance vision in individuals who still retain some accommodative function. While these general miotic agents also create improved depth of focus via a pinhole effect induced by pupillary miosis (i.e. constriction), to the degree accommodation occurs, the pinhole effect only partially offsets the induced accommodative myopia for distance. In some cases, such as with pilocarpine or carbachol, the induced accommodation may create up to 5 diopters or more of induced myopia resulting in induced myopia causing blurred distance vision generally and during shift of the focal point from distance to near. These general miotic agents also cause substantial redness, severe nasal congestion and create ciliary muscle spasms, which commonly induces discomfort that can be severe and long-lasting. In extreme cases, such ciliary muscle spasms can result in retinal detachment.
The holy grail of topical induced presbyopic correction results in no reduction in distance vision. Currently all miotic agents (e.g. muscarinic agonists) cause a reduction in distance vision by converting points of distance focus to a near point. Miotic agents enhance near vision in this manner through contraction of the ciliary muscle, particularly the circumferential radial component, however this same contraction thereby causes reduction in distance vision. Distance vision is reduced by as much as 5 to 11 diopters (e.g. pilocarpine 2%-4%) in some cases, particularly for those with some residual near focus (accommodation). While this can be modulated by reducing the concentration of the miotic agent, the degree of ciliary induced accommodation is thereby also reduced limiting the closeness of the near point of focus. Further, any advantage of increased depth of focus from pinhole optics that might enhance both distance and near vision requires sufficiently great pupil constriction. This pupil constriction requires higher concentrations of muscarinic agonists than the distance blur resulting from even modest concentrations will allow.
Miotic agents have been described in various patent and patent applications for the treatment of presbyopia. U.S. Pat. Nos. 6,291,466 and 6,410,544 describe the use of pilocarpine to regulate the contraction of ciliary muscles to restore the eye to its resting state and potentially restore its accommodative abilities.
US Patent Application Publication No. 2010/0016395 describes the use of pilocarpine with the non-steroidal anti-inflammatory, diclofenac, to reduce brow ache from ciliary spasm, but does not prevent induced miosis and distance blur. International PCT Application Publication WO/2013/041967 describes the use of pilocarpine with oxymetazoline or meloxicam to temporarily overcome ocular conditions such as presbyopia and possibly slightly decreases the degree of ciliary muscle contraction due to reduced pilocarpine levels in the ciliary body due to vasoconstriction of the ciliary vasculature. Specifically, ciliary induced miosis results in about 0.7 lines of distance vision loss, equating to an eye that is reduced to 20.27 distance vision. This reduction is about a 26% drop in distance acuity from the otherwise 20.20 best corrected vision.
U.S. Pat. No. 8,299,079 (HEK Development LLC) describes the use of direct acting general miotic agents such as pilocarpine, carbachol and phospholine iodide with brimonidine at a concentration from 0.05% to 3.0% w/v. However, the use of brimonidine concentrations at or above 0.05% w/v results in increased dryness and with regular use possible rebound hyperemia. For example, rebound redness occurs in 25% of patients using brimonidine 0.20% w/v (Alphagan®, registered trademark of Allergan, Inc.) twice daily. Further brimonidine only slightly reduces dilation of the pupil in scotopic conditions, does not enhance its constriction or affect ciliary induced myopia.
US Patent Application No. 2014/0113946 (Allergan®) discloses means of treating presbyopia using pilocarpine and an alpha agonist, such as oxymetazoline. Examples using pilocarpine 1.0% disclose a loss of 0.7 lines of average distance vision (26% reduction) and demonstrate pupil constriction greater than 2.0 millimeters (“mm”) at all time points, ranging from 2.1 to 3.2 over a six hour period. Oxymetazoline concentrations in preferred embodiments of 0.05% and 0.125% are both at or above concentrations known to be associated with rebound hyperemia (0.05%) and labeled for maximum daily use of three days (Visine L.R.®; Visine L.R. is a registered trademark of Johnson & Johnson Corp.).
These attempts at miotic treatment for presbyopia all induce transient myopia of reducing distance vision by 20% or worse for many subjects, caused by ciliary contraction. These attempts also often induce bothersome and not infrequently painful ciliary brow ache analogous to a moderately severe migraine. In some cases, miotic treatments induce improved near vision that begins deteriorating within a few hours (i.e. US 2014/0113946 loss of effect starting at about 4 hours and degrading rapidly).
Current efforts to achieve presbyopic treatment with miotic agents are limited by the accommodative distance blur and ciliary induced brow ache that severely limit usefulness. Specifically, due to the need for lower concentrations that may somewhat reduce but not eliminate these bothersome side effects, only limited pupillary miosis occurs. This limited pupillary miosis limits depth of focus pinhole optic benefit to near vision and distance vision. Both distance and near optimal vision potential is compromised. Additionally, this limited pupillary miosis is sufficient only to partially offset the distance blur resulting from greater near point of focus. Further, only a few hours duration of this limited action can be achieved. Thus, there is a need in the art for a treatment of presbyopia that is non-invasive and convenient with minimal side effects. Specifically, there is a need for an opthalmological composition that will allow a person suffering from presbyopia to focus on near objects without significant side effects such as diminished distance vision, blurred vision, pain, and redness, impaired night driving or incapacitating dim light vision, induced nasal congestion, or risk of retinal detachment.